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CELL SCIENCE AT A GLANCE

Human mitochondrial COX1 assembly into cytochrome c oxidaseat a glance

Sven Dennerlein1 and Peter Rehling1,2,*

ABSTRACT

Mitochondria provide the main portion of cellular energy in form of

ATP produced by the F1Fo ATP synthase, which uses the

electrochemical gradient, generated by the mitochondrial

respiratory chain (MRC). In human mitochondria, the MRC is

composed of four multisubunit enzyme complexes, with the

cytochrome c oxidase (COX, also known as complex IV) as the

terminal enzyme. COX comprises 14 structural subunits, of nuclear

or mitochondrial origin. Hence, mitochondria are faced with the

predicament of organizing and controlling COX assembly with

subunits that are synthesized by different translation machineries

and that reach the inner membrane by alternative transport routes.

An increasing number of COX assembly factors have been

identified in recent years. Interestingly, mutations in several of

these factors have been associated with human disorders leading to

COX deficiency. Recently, studies have provided mechanistic

insights into crosstalk between assembly intermediates, import

processes and the synthesis of COX subunits in mitochondria, thus

linking conceptually separated functions. This Cell Science at a

Glance article and the accompanying poster will focus on COX

assembly and discuss recent discoveries in the field, the molecular

1Department of Cellular Biochemistry, University Medical Center Gottingen,37073 Gottingen, Germany. 2Max-Planck Institute for Biophysical Chemistry,37077 Gottingen, Germany.

*Author for correspondence (peter.rehling@medizin.uni-goettingen.de)

� 2015. Published by The Company of Biologists Ltd | Journal of Cell Science (2015) 128, 833–837 doi:10.1242/jcs.161729

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functions of known factors, as well as new players and control

mechanisms. Furthermore, these findings will be discussed in the

context of human COX-related disorders.

KEY WORDS: COX1, MITRAC, Mitochondria, Cytochrome c

oxidase, Complex IV

IntroductionMitochondria are double-membrane-bounded organelles thatoriginated from a bacterial ancestor through endosymbiosis.The outer and inner mitochondrial membranes (OMM and IMM)segregate mitochondria into two aqueous compartments, the

mitochondrial matrix and the intermembrane space (IMS). Theinner mitochondrial membrane forms cristae, which extend intothe matrix and harbor the mitochondrial respiratory chain

complexes and the F1Fo ATP synthase at the cristae tips(Davies et al., 2013). In human mitochondria, complex I(NADH dehydrogenase) represents the largest respiratory chain

complex with a size of 1 MDa; it consists of 44 structuralsubunits, seven of which are mitochondrially encoded (Hunteet al., 2010; Vinothkumar et al., 2014). In contrast to complex I,the smallest complex, complex II (succinate dehydrogenase) is

composed of only four nuclear-encoded proteins. Complex III(bc-complex), which contains one mitochondrially (cytochromeb) and ten nuclear-encoded subunits, reduces cytochrome c,

thereby providing electrons to the cytochrome c oxidase (COX,also known as complex IV). Cytochrome c oxidase is the terminalenzyme of the respiratory chain and electrons are transported by

four redox-active centers (two copper centers and two heme a

moieties) to molecular oxygen. In addition, COX contains severalmetal ions with yet unknown functions. Of the 14 structural

subunits, the three core components, COX1, COX2 and COX3(also known as MT-CO1, MT-CO2 and MT-CO3, respectively)are synthesized within the organelle, where they need to assemblewith nuclear-encoded, peripherally localized subunits of the

enzyme complex. An increasing number of factors required forcytochrome c oxidase assembly have been identified in recentyears and mutations in the corresponding genes have been

associated with various human diseases that are caused bydeficiency of the enzyme complex. Interestingly, many of theseproteins lack a clear yeast homolog.

Recent studies have provided unexpected insights into thebiogenesis of mitochondrially encoded subunits and how thisprocess is integrated into regulatory cycles. Here, we will first

give a general overview of the complexes involved in COXassembly. Then we will illustrate the human mitochondrial TIM23transport machinery and how it cooperates with COX assemblyintermediates (see poster). As the assembly pathway of COX

differs between yeast and human, we will compare these systems.We will then discuss the human COX1 assembly pathway in moredetail and finally summarize known human diseases that are linked

to COX deficiency.

The human presequence translocase – the TIM23 complexMitochondrial protein translocases that are responsible for theimport of nuclear-encoded COX subunits into the mitochondriadisplay high evolutionary conservation. Studies of themechanisms underlying the transport processes have largely

exploited yeast as a model organism (Chacinska et al., 2009;Dolezal et al., 2006; Dudek et al., 2013; Endo et al., 2011;Neupert and Herrmann, 2007; Sokol et al., 2014). However, the

last few years have revealed several differences between thehuman and the yeast protein transport machineries. DNAJC19 and

MCJ (also known as DNAJC15) initially have been considered torepresent putative human orthologs of the yeast Pam18 protein,a component of the TIM23-complex-associated import motorthat drives transport of precursors into mitochondria (D’Silva

et al., 2008; Kozany et al., 2004; Li et al., 2004). Moreover,yeast Pam18 and its regulator Pam16 have been found to associatewith respiratory chain complexes (Wiedemann et al., 2007).

Defects in DNAJC19 have been linked to the syndrome dilatedcardiomyopathy with ataxia (DCMA), a severe cardiomyopathy(Davey et al., 2006; Ojala et al., 2012). However, recent studies

have shown that the majority of DNAJC19 associates withprohibitin complexes in human mitochondria and that DNAJC19participates in cardiolipin metabolism (Richter-Dennerlein et al.,

2014). Moreover, apart from its function in protein transport,another function of DNAJC19 that is not related to proteintransport is further supported by the observation that only thesecond putative yeast Pam18 ortholog, MCJ, rescues pam18D cells

(Schusdziarra et al., 2013). Strikingly, it has also been suggestedthat MCJ regulates the activity of complex I and promotesincorporation of complex I into respiratory chain supercomplexes

(Hatle et al., 2013). These observations suggest that MCJ is presentin two independent pools, because an association of the TIM23complex with respiratory chain supercomplexes has not been

described in humans. Nevertheless, it remains to be shown whetherthe observed interactions of MCJ with complex I and the TIM23complex reflect a dynamic behavior.

Interestingly, TIM21 has been recently found to undergodynamic associations between the TIM23 complex and COXassembly intermediates (Mick et al., 2012). TIM21 is a conservedsubunit of the human TIM23 complex, but it also associates with

the MITRAC (mitochondrial translation regulation assemblyintermediate of COX) complex, an early assembly intermediate ofthe COX (see poster). TIM21 ushers imported, early COX

subunits from the TIM23 complex to MITRAC (Mick et al.,2012) (see poster). The interaction between TIM21 and theTIM23 complex depends on active protein import, as a block of

cytosolic translation inhibits the TIM23–TIM21 interaction, butdoes not affect the association of TIM21 with MITRAC. Bycontrast, a block in mitochondrial translation reduces theinteraction of TIM21 with MITRAC, without affecting the

interaction with TIM23.

Mitochondrial COX1 gene expression in yeast and humanThe mitochondrial gene expression system differs substantiallybetween lower and higher eukaryotes. The ribosome ofmammalian mitochondria is a 55S particle with a 28S small

subunit (mtSSU) and a 39S large subunit (mtLSU). In contrast,the yeast mitochondrial 70S ribosome comprises of a 37S SSUand a 54S LSU, respectively (for reviews, see Hallberg and

Larsson, 2014; Lightowlers et al., 2014). Considering thesedifferences, it is not surprising that fundamental changes in thesynthesis and regulation of mitochondrial proteins have takenplace during evolution. This section will focus on the translation

of the COX1 protein by providing a short overview of Cox1synthesis and regulation in yeast and summarizing the currentview on the synthesis of human COX1.

In Saccharomyces cerevisiae, the mitochondrial mRNAscontain 59UTRs that are recognized by specific translationalactivator proteins. In the case of COX1 mRNA, these activators

are Mss51 and Pet309 (Barrientos et al., 2004; Perez-Martinez

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et al., 2003; Tavares-Carreon et al., 2008; Zambrano et al., 2007;Zamudio-Ochoa et al., 2014). Pet309 belongs to the pentatricopeptide

repeat (PPR) protein family, which is typically involved in mRNAmetabolism. Pet309 has been shown to bind COX1 mRNA and isrequired for its translation (Manthey and McEwen, 1995; Tavares-Carreon et al., 2008; Zamudio-Ochoa et al., 2014). Mss51 is able to

bind to COX1 mRNA, as well as to the newly synthesized Cox1protein (Barrientos et al., 2004; Perez-Martinez et al., 2003; Perez-Martinez et al., 2009; Zambrano et al., 2007). Oxa1 facilitates

insertion of Cox1 into the inner mitochondrial membrane. The firstassembly step of newly synthesized Cox1 is its association with thetwo small inner membrane proteins, Cox14 and Coa3, as well as

Mss51, forming a COX assembly intermediate (Mss51SA complex)(Fontanesi et al., 2011; Mick et al., 2011) (see poster). Subsequently,several other proteins, among them Coa1, Shy1 and the nuclear-

encoded Cox5 and Cox6 subunits, engage with the maturing COXcomplex. These steps also involve heme integration into Cox1,although it is not clear at which state precisely the incorporationoccurs. A detailed overview of predicted COX assembly steps in

yeast mitochondria can be found in recent reviews (e.g. Mick et al.,2011; Fontanesi, 2013).

The synthesis of COX1 in humans appears to differ significantly

from the process in yeast (see poster). In contrast to yeast,mammalian mitochondrial mRNAs lack significant 59UTRregions. Upstream of the translational start codon ATG, COX1

mRNA contains only three nucleotides in its 59 region (Temperleyet al., 2010). Thus, it appears unlikely that translational activatorsequivalent to yeast Pet309 or Mss51 could bind to the mRNA.

Not surprisingly, no robust homologs of the translationalactivators have so far been identified in metazoa. Taking thisinto consideration, it is expected that alternative regulatorymechanisms for COX1 expression exist in human mitochondria.

The PPR-motive containing human protein LRPPRC, displayslow sequence similarity to yeast Pet309 (Mootha et al., 2003;Sasarman et al., 2010). LRPPRC forms a mitochondrial

ribonucleoprotein (RNP) complex with steroid receptor RNAactivator (SRA) stem-loop interacting protein (SLIRP) in humanmitochondria. This RNP complex interacts with polyadenylated

mRNAs and is required for mitochondrial mRNA stability. Infibroblasts of patients with French–Canadian Leigh syndrome(LSFC), an early-onset progressive neurodegenerative disorderthat is caused by mutations in LRPPRC, a specific reduction in

the levels of COX has been observed (Sasarman et al., 2010).However, recent studies have shown that there is a tissue-specificinvolvement of LRPPRC in the assembly of respiratory chain

complexes. Recently, in heart mitochondria of a conditionalknockout mouse, a reduction of COX and impaired assembly ofthe F1Fo ATP synthase has been observed (Mourier et al., 2014).

When loss of LRPPRC function was assessed in different humantissues, the fibroblasts of LSFC patients displayed primarily a COXdeficiency. However, upon a more severe reduction of LRPPRC

levels, the entire respiratory chain was affected (Sasarman et al.,2015). Muscle cells from LSFC patients showed a combinedNADH dehydrogenase and COX defect, whereas human heart-derived cells were only had mildly affected COX activity.

Moreover, COX was almost undetectable in liver, underlining theimportance of LRPPRC for COX maturation in specific organs. It istherefore tempting to speculate that tissue-specific pathways for the

post-transcriptional handling of mitochondrial mRNAs exist.The only known COX1-specific translation-regulating factor in

higher eukaryotes is TACO1 (Weraarpachai et al., 2009) (see

poster). Fibroblasts of patients with compromised TACO1

function present a slowly progressive Leigh syndrome and areduction of COX1 synthesis that is concomitant with a faster

turnover of COX2 and COX3. This finding clarifies the molecularbasis of COX deficiency in these patients. However, themolecular function of TACO1 and how it affects COX1synthesis on a biochemical level is still unknown.

COX assembly – COX1 takes center stageThe crystal structure of the bovine COX complex originally

revealed 13 structural subunits (Tsukihara et al., 1996). However,recently a 14th subunit, NDUFA4, has been described and needsto be considered as a COX component (Balsa et al., 2012;

Pitceathly et al., 2013). The biogenesis of the COX, just as for otherOXPHOS complexes, depends on the coordinated assembly ofproteins encoded in the nucleus and mitochondria. This assembly

process requires specific factors that protect cells from damage,stabilize complex intermediates and promote enzyme maturation.In S. cerevisiae, more than 20 proteins have been described to beinvolved in the maturation of COX (Barrientos et al., 2009; Kim

et al., 2012; Mick et al., 2011). Only a few of these have beenidentified in humans. Our current knowledge of COX assemblyfactors is mainly based on the analysis of patients with complex IV

deficiency or on homology to yeast proteins. A bioinformatic studyexploiting yeast proteins identified C12orf62 as displayingsequence similarity to yeast Cox14 (Szklarczyk et al., 2012). At

the same time, a patient with a defect in C12orf62, presenting withfatal neonatal lactic acidosis, was identified (Weraarpachai et al.,2012). However, although loss of Cox14 in yeast leads to increased

synthesis of Cox1, which is subsequently degraded, loss ofC12orf62 leads to a decrease in COX1 translation, suggestingthat the function of the yeast Cox14 protein and the supposedhuman homolog C12orf62 are different and even provoke opposite

effects upon protein loss (Clemente et al., 2013; Fontanesi et al.,2011; Mick et al., 2012; Weraarpachai et al., 2012).

The MITRAC complex has been identified as a COX assembly

intermediate, integrating mitochondrially encoded and newlyimported proteins (see poster). Because maturation of the enzymecomplexes is a sequential process during which new components

and cofactors are added, the composition of the MITRACcomplex changes during the process. Current data indicate thatearly-MITRAC contains C12orf62 and MITRAC12, and assistsCOX1 in early assembly steps. TIM21 is likely to incorporate

newly imported COX subunits into MITRAC at a later stage.However, precisely at which stage the interaction with TIM21occurs and how the COX1 translational feedback mechanism is

mediated remains unknown.Several other proteins, many of which have been identified in

the course of investigations of patients with a COX deficiency,

have been described during the last decade. However, themolecular function for these proteins in COX biogenesis isoften elusive. One of the most prominent examples is SURF1, for

which a large number of mutations that lead to COX deficiencyhave been identified in patients (for a review, see Wedatilakeet al., 2013). Patients with SURF1 mutations also display thephenotype of Leigh syndrome. In most cases, the disease is

caused by instability of the SURF1 protein and a reduction in theamount of fully matured COX, although a concomitantaccumulation of subcomplexes have been observed in these

patients. Studies on SURF1 in bacteria and yeast indicate that theprotein is involved in the insertion or stabilization of the heme-containing cofactors of COX1 (Bareth et al., 2013; Smith et al.,

2005).

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Two other proteins, C2orf64 and PET100 (also known asC19orf79), are potentially involved in the COX1 assembly

process. A mutation in the C2orf64-encoding gene (COA5) leadsto an accumulation of various COX assembly intermediates andreduced steady-state levels of COX1, thus explaining the complexIV deficiency (Huigsloot et al., 2011). A similar phenotype is

observed in patients with mutations in the PET100 gene (Limet al., 2014; Olahova et al., 2014). PET100 is present in a300 kDa complex together with other subunits of the COX (Lim

et al., 2014). However, the function of PET100 is still elusive.

Concluding remarksSeveral factors involved in COX assembly have been identified

recently and add new insights into the molecular details of thisprocess. However, considering the complexity of the assemblyprocess, very little is currently known about the sequences of

events and the function of the assembly factors. Theestablishment of new techniques such as exome sequencing willhelp to identify new players. Although this is certainly essentialfor a comprehensive understanding, the challenge lies in the

determination of the exact functions of the various proteins. Todate we are still far from explaining how the COX1 protein ishandled throughout the assembly process.

However, recent studies, as discussed above, provided abroader insight the COX1 assembly process and so bring uscloser to a biochemical understanding of human diseases. These

data could be the basis of further drug development and so mightpave the way for COX therapy.

AcknowledgementsWe are grateful to S. Callegarie and R. Richter-Dennerlein for critical commentson the article.

Competing interestsThe authors declare no competing or financial interests.

FundingWork in our laboratory is supported by the Deutsche Forschungsgemeinschaft;European Research Council [grant number 339580] to P.R.; and the Max-Planck-Society (to P.R.).

Cell science at a glanceA high-resolution version of the poster is available for downloadingin the online version of this article at jcs.biologists.org. Individualposter panels are available as JPEG files athttp://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.161729/-/DC1.

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